A polymer widely used as a gene transfection reagent may also represent an effective adjuvant for mucosal vaccines against pathogens such as flu, HSV-2, or HIV-1, researchers claim. Studies in experimental mice have shown that when complexed with polyethyleneimine (PEI), a single dose of an intranasally administered glycoprotein antigen vaccine against either flu or HSV-2 helped trigger robust antibody-mediated immune responses that protected the animals against otherwise lethal infections. The adjuvant also appears safe and doesn’t trigger inflammatory responses at mucosal surfaces, report Quentin J. Sattentau, M.D., at the University of Oxford’s Sir William Dunn School of Pathology, and colleagues. “Gaining complete protection against flu from just one immunization is pretty unheard of, even in a study in mice,” Dr. Sattentau says. “This gives us confidence that PEI has the potential to be a potent adjuvant for vaccines against viruses like flu or HIV.”
The investigators detail their work in Nature Biotechnology, in a paper titled “Polyethyleneimine is a potent mucosal adjuvant for viral glycoprotein antigens.”
No adjuvanted mucosal vaccines targeting major mucosally transmitted infectious diseases have yet been licensed for human use. Although there are a variety of investigational mucosal adjuvants in development, including bacterial toxin subunits and receptor agonist-based adjuvants, these are also associated with safety concerns linked with local or systemic toxicity, the researchers write.
In contrast, PEI is a cationic polymer than can be synthesized as linear, branched, high- or low-molecular weight species. The polymer forms complexes with nucleic acids that bind cell surface heparin sulphate proteoglycans and enter cells through endocytosis. Interestingly, PEI has also been shown to increase the immunogenicity of DNA vaccines.
The fact that PEI can deliver a cargo into cells—such as antigen-presenting cells (APCs)—that express heparin sulphate proteoglycans, the Oxford University-led team postulated that the polymer may also function as a mucosal adjuvant for glycoprotein antigens. Their initial studies in mice compared intranasal immunization using a weakly immunogenic experimental recombinant envelope gp140 glycoprotein HIV-1 antigen. The antigen vaccine was given twice, either alone or as a complex with different forms of PEI, or with a known mucosal adjuvant, CTB (cholera toxin B subunit).
The results showed that animals immunized using the PEI-adjuvanted vaccines generated up to 100-fold higher antigen-specific serum IgG titers than those administered with just the gp140 antigen, and up to six times higher titers than animals receiving a CTB-adjuvanted antigen. A single dose of the intranasally administered PEI-vaccine complex was also safe and similarly immunogenic, while further studies showed that the adjuvant doesn’t induce the production of proinflammatory cytokines, indicating that it’s unlikely to elicit damaging inflammatory reactions at mucosal surfaces.
Encouragingly, the most promising gp140-PEI vaccine, which included a branched PEI polymer, was more effective in mice than vaccines generated using other adjuvants, and led to animals raising antibodies specific to gp140 in its native conformation. When tested in rabbits, the PEI-complexed vaccine similarly led to much higher titers of protective antibodies than vaccines generated using other adjuvants.
The researchers subsequently showed that an intranasally administered PEI-adjuvanted flu vaccine (purified influenza A/PR8 hemagglutinin) protected mice against a pathogenic intranasal dose of the virus, and also provided complete protection against an otherwise lethal dose. Importantly, intranasal administration of a PEI-adjuvanted HSV-2 vaccine protected animals against vaginal challenge with an otherwise lethal dose of the herpes virus, demonstrating that administration of the vaccine via one mucosal surface can provide protection against infection via a different mucosal route.